Glaucoma is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is the most significant risk factor contributing to death of retinal neurons and resulting visual field loss in primary open angle glaucoma, the most common form of glaucoma. The current standard of care for glaucoma includes IOP- lowering medications delivered topically as eye drops, which decrease the volume of aqueous humor either through inhibition of its production or enhancement of its drainage. No current therapies affect both production and drainage. Because of their short half-lives and limited residence time on the cornea, dosing is required from one-to-three times daily, which significantly limits patient compliance and also increases the incidence of orbital and systemic side effects. Using a systems genetics approach, we have: 1) identified CACNA2D1 as a new ocular target for lowering IOP; 2) demonstrated that pregabalin exhibits potent IOP-lowering activity; 3) shown that uptake properties of pregabalin limit systemic exposure without affecting ocular diffusion; and 4) developed a pregabalin microemulsion formulation that can be delivered in an extended release formulation to decrease the number of doses required by current treatments. At OculoTherapy, we will address the major limitations of current IOP therapy by advancing our development of a sustained-release IOP-lowering formulation that coordinates multiple targets including the ciliary body and trabecular meshwork to normalize IOP. This treatment strategy will reduce the burden to the patient, increase compliance and lead to better visual outcomes for glaucoma patients. Our central hypothesis is that pregabalin?when formulated in a topical microemulsion with characteristics of sustained release, bioadhesion, and corneal penetration enhancement?will elicit an IOP-lowering response that is equal to or greater in amplitude, and significantly greater in duration, than other glaucoma medications currently on the market. In this Phase I SBIR proposal we will provide proof of concept and address key feasibility questions by establishing efficacy, pharmacodynamics, biocompatibility and biodistribution of our pregabalin microemulsion. We will establish minimum performance endpoints based on the efficacy of various concentrations of single- dose, topically applied pregabalin microemulsion to achieve maximal IOP reduction. We will also establish efficacy of repeated daily dosing of pregabalin microemulsion for 21 days to sustain IOP at a level equal to the maximal reduction achieved by a single dose within 24 hrs. We will also establish intraocular (as well as whole- body) distribution of pregabalin after 21 days of topically applied microemulsion. Our minimum performance end point will include the demonstration that pregabalin targets the ciliary body and trabecular meshwork. Based on our preliminary data, we anticipate that our SBIR Phase I work will validate the proof of concept for pregablin microemulsion therapy for treatment of elevated IOP. These studies will position us to proceed directly to a Phase II demonstration project in preparation for Phase IIB and/or Phase III commercialization.